2008 Grants - Pimplikar

The Role of APP Intracellular Domain in Neuronal Excitotoxicity

2008 Investigator-Initiated Research Grant

Amyloid precursor protein (APP) is the parent molecule of beta-amyloid, a key suspect in Alzheimer's disease. APP is a transmembrane protein, which means portions of it exist both inside and outside a cell. Beta-amyloid is clipped from APP and remains outside the cell. Recently, Alzheimer research has focused on the APP fragment that remains inside the cell, called the APP intracellular domain (AICD). AICD appears to affect cell function in various ways, and it may contribute to the development of Alzheimer's disease.

In earlier studies, Sanjay W. Pimplikar, Ph.D., and colleagues have developed mice that generate elevated levels of AICD. They found that these mice produce glycogen synthase kinase 3, a protein linked to harmful protein tangles in the Alzheimer brain. These mice also showed other Alzheimer-related pathologies, including abnormal electrical communication between brain cells and an increased incidence of brain seizures. Taken together, the researchers' findings suggest that AICD is responsible for certain pathological features of Alzheimer's disease.

For this proposal, Dr. Pimplikar and colleagues will use their engineered mice to study the association of AICD with abnormal electrical activity in the brain. They will also examine AICD links with a phenomenon called excitotoxicity, in which certain proteins overstimulate neurons and cause neuronal damage and death. The researchers hope to determine biological mechanisms underlying these possible links. Finally, the team will study how abnormal AICD affects brain cells in a variety of mouse models engineered to develop Alzheimer-like symptoms.

Results of Dr. Pimplikar's effort could shed new light on the complex role that APP plays in Alzheimer's disease. Such knowledge could lead to novel Alzheimer therapies.